Process for preparation of dronedarone by oxidation of a hydroxyl group

ABSTRACT

The invention relates to a novel process for the preparation of dronedarone (I) and pharmaceutically acceptable salts thereof 
     
       
         
         
             
             
         
       
         
         
           
             which comprises oxidizing a compound of formula (VI), or a salt thereof 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof. 
           
         
       
    
     Further aspects of the invention include the novel intermediary compound of formula (VI) and process for the preparation thereof.

FIELD OF THE INVENTION

The invention relates to a novel process for the preparation ofdronedarone and pharmaceutically acceptable salts thereof, to novelintermediary compounds used in this process and their preparation.

TECHNICAL BACKGROUND

Dronedarone, i.e.N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide,having the formula (I):

is a known drug for the treatment of arrhythmia (EP0471609).

There are some known processes for the preparation of dronedarone asfollows:

In EP 0471609 the following scheme is disclosed for the preparation ofdronedarone

[Process A]

The above mentioned patent description discloses some new intermediarycompounds, too.

In WO 02/48078 the following scheme is disclosed for the preparation ofdronedarone

[Process B]:

The novelty of the process is based on the adaptation of theFriedel-Crafts reaction in the first step. The process and theintermediary compounds used for the preparation of the benzoylchloridecompound of the first step are also disclosed in this document. Thefurther steps of the process are identical with the final steps of thesynthetic route disclosed in EP 0471609 [Process A], but in the claimsthe whole synthetic route is claimed, up to dronedarone.

In WO 02/48132 (Sanofi) the following reaction route is disclosed[Process C]. This method is the so called superconvergent route. In thefirst step of it 5-amino-2-butyl-benzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran(in HCl salt form) is further reacted in the next step as follows:

In this process the order of reaction steps are altered, the reductionand the methansulfonylation steps are performed at the beginning part ofthe procedure. Besides the reaction route for preparation ofdronedarone, the starting material2-butyl-5-methansulfonamido-benzofuran and its preparation are alsoclaimed.

From among the mentioned procedures the first one [Process A] is the socalled linear synthesis. In this way of procedure the different parts ofthe dronedarone are stepwise built up on the starting compound. Thismethod is the least economical because the continuous step by stepbuilding of the chemical groups is performed on more and morecomplicated and expensive molecules, which raises the costs of thepreparation.

Furthermore it comprises complicated and harmful reaction steps becausealuminium chloride is used in the cleaving reaction of the methoxy groupwhich makes the industrial feasibility more complicated.

In WO 02/48078 (Process B) a shorter synthetic route is disclosed whichmakes this process more economical, but its last reaction step remainedthe methansulfonylation reaction of the amino group. This reaction step(see the method described in example 6 of WO 02/48078) is complicatedand gives a low yield of only 61.6%. Pure product can be expected afterpurification using chromatographic column purification, which method isnecessary because of the separation difficulties of thebis-methanesulfonylated product.

The process disclosed in WO 02/48132 (process C) is simpler and moreeconomical taking into consideration the number of the reaction steps.Unfortunately, in the last reaction step rather impure dronedarone.HCl(hydrochloride salt) is formed which is the obvious consequence of thepresence of the dibutylamino group in the Friedel-Crafts reaction.According to Examples 3 and 4, the crude dronedarone hydrochloride saltis prepared with a yield of 90% which is further purified and finallythe crude dronedarone base is produced with a yield of 86%. This base isreacted with hydrogen chloride gas dissolved in isopropanol whichresults in pure dronedarone hydrochloride salt. No yield is given forthis reaction step. According to example 5 crude dronedaronehydrochloride salt is prepared with a yield of 90%, which is washed withwater and reacted with hydrogen chloride gas dissolved in isopropanol,resulting dronedarone hydrochloride salt again. The quality of thisproduct is not known. However, since neither the components used in theFriedel-Crafts reaction nor the resulting products and by-products aresoluble in water, the washing step with water cannot result anypurification apart from the removal of inorganic salts.

There is another drawback of this process, namely, a dimesylatedside-product is formed in the mesylation reaction of the5-amino-2-butyl-benzofuran. The purification is carried out bycrystallization which has a yield of 78.5%.

It is an object of the present invention to provide a novel process forthe preparation of dronedarone (I), starting from known and commerciallyavailable materials, applying simple, environmentally compatiblereagents and solvents, to afford high overall yields and good purity ofthe product.

SUMMARY OF THE INVENTION

The main aspect of the invention is a process for preparation ofdronedarone (I) and pharmaceutically acceptable salts thereof

which comprises oxidizing a compound of formula (VI), or a salt thereof

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

We have surprisingly found that the formation of the oxo group in thelast step by oxidation of an OH group which is formed by aldolcondensation of substituted benzofuran and an aldehyde, has severalbenefits. Namely, the advantages of this process compared to thepreviously mentioned [A] and [B] processes are that the Friedel-Craftsacylation of 2-butyl-5-nitrobenzofuran can be avoided and the processdoes not use harmful reagents such as AlCl₃ or FeCl₃. Furthermore, thefinal oxidation step with hydrogen peroxide is a pure process with goodisolated yield.

Further aspects of the invention include the compound of formula (VI) asa new compound, its salts and process for the preparation thereof (seebelow in the “Detailed description of the invention” part).

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to a process for the preparationof dronedarone and pharmaceutically acceptable salts thereof. The wholeprocess—starting from known compounds—reads as follows:

(a) a compound of formula (II)(N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide) is reacted with thecompound of formula (V) in the presence of strong acid or base catalystto obtain a compound of formula (VI):

(b) the compound of formula (VI)(N-(2-butyl-3-{[4-(3-dibutylamino-propoxy)-phenyl]-hydroxymethyl}-benzofuran-5-yl)-methanesulfonamide)is oxidized to obtain dronedarone (I),

and the obtained product is isolated and, if desired, converted into apharmaceutically acceptable salt thereof.

The intermediate (VI) is a new compound and is isolated in pure solidform. Said compound, its salts and its preparation process [i.e. theabove step (a)] form further objects of the invention.

Compound of formula (V) is known from J. Med. Chem. 1988, 31 (9) 1778.It can be prepared as described in the following:

a compound of formula (III) (4-hydroxybenzaldehyde) is reacted with acompound of formula (IV) (dibutylamino propylchloride HCl salt)

and the obtained compound of formula (V) is isolated and, if desired,converted into a pharmaceutically acceptable salt thereof.

This reaction is typically carried out in a solvent or in a mixture ofsolvents. The solvent is typically selected from the group of ketones,esters and any mixtures thereof. Specific examples include, amongothers, methyl ethyl ketone or ethyl acetate.

The reaction is typically carried out in the presence of a base. Saidbase is typically selected from the group of alkali carbonates, e.g.potassium carbonate.

The reaction temperature may range from room temperature to the boilingpoint of the reaction mixture, typically a heating to 70-90° C. isapplied.

Compounds of formula (II) and (IV) are known from WO 02/48132 (Sanofi).

Compound of formula (III) is commercially available.

Step (a) of the process of the invention is carried out in the presenceof a strong acid or base catalyst. Examples of the catalysts aretrifluoracetic acid and butyl lithium.

Typically, step (a) is carried out in a solvent. The solvent may be aninert solvent (e.g. hexane, THF or MeTHF) or may serve as the catalyst(e.g. trifluoracetic acid).

The oxidation of step (b) is typically carried out in a solvent, in thepresence of an oxidizing agent. The oxidizing agents can be for examplesodium hypochlorite or hydrogen peroxide in aqueous acidic medium. Ifdesired, the excess of the oxidizing agent (e.g. sodium hypochlorite)can be neutralized by using e.g. sodium bisulfite.

In the above reactions the temperature is chosen according to thegeneral practice of a person skilled in organic chemistry. Applicabletemperature values can be found in the examples.

The reaction steps are generally carried out under atmospheric pressure.

In the processes for the preparation of the intermediary compounds offormula (V) and (VI) the product is typically isolated as a base. Ifdesired, the isolated base can be converted into a salt (acid additionsalt) thereof, which is typically a pharmaceutically acceptable salt(possible acids are mentioned below). Theoretically the acid additionsalt can be prepared directly if the relating acid is in the finalreaction mixture from which the solid product is made (however, this wayis not applied in case of these compounds where the base type form haspractical importance).

The applicable acid for the preparation of pharmaceutically acceptablesalts can be any inorganic or organic acid which forms an acid additionsalt with the compound of general formulae (I), (V) and (VI). Exemplaryacids which can form an acid addition salt are as follows: acetic acid,adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid,benzenesulfonic acid, boric acid, butyric acid, citric acid,ethanesulfonic acid, fumaric acid, hydrogen chloride, hydrogen bromide,hydrogen iodide, 2-hydroxyethanesulfonic acid, maleic acid, oxalic acid,methanesulfonic acid, nitric acid, salicylic acid, tartaric acid,sulfuric acid (forming sulfate or bisulfate anion), sulfonic acid (suchas those mentioned herein), succinic acid, toluenesulfonic acid and thelike. The hydrogen halogenide salts are typical, especially the hydrogenchloride salt.

Here it is mentioned that on the mesylate group of compounds of generalformulae (I) and (VI) (see the “left side” of the molecules) a saltformation can be carried out (on the amide part of it) by a strong base,e.g. an alkaline hydroxide, typically by sodium hydroxide. However,these salts have less practical importance, but they are within thescope of salts. It means that the phrase “salts” embraces both the acidaddition salts and the salts formed by bases (basic salts) in case ofcompounds of formula (I).

The following non-limiting examples further illustrate the invention.

In the examples the following HPLC method was applied for thedetermination of the purity of the reaction products:

Column: Waters Symmetry C18 4.6×150 mm, 5 μm

Mobile phases:

-   -   Mobile phase A: 5 mM sodium phosphate buffer, pH=2.2    -   Mobile phase B: acetonitrile    -   Mobile phase C: methanol

Column temp: 25° C.

Auto sampler temp: 20° C.

Gradient:

Time (min) A (%) B (%) C (%) 0 65 30 5 20 40 50 10 45 15 75 10 47 65 305 57 65 30 5

Injection vol: 10 μL

Flow rate: 1.5 mL/min

Run time: 57 min

Detection: 245 nm

Preparation Preparation 1 4-(3-dibutylamino-propoxy)-benzaldehyde (V)

9.69 g of dibutylamino propylchloride HCl salt (IV) (0.04 mol, 1 eq), 5g of 4-hydroxybenzaldehyde (III) (0.04 mol, 1 eq), 17 g of potassiumcarbonate (0.12 mol, 3 eq) and 30 mL of MEK are added to the reactionflask. The suspension is heated to 80° C. and it is stirred for 10 hoursat this temperature. Then the mixture is cooled to room temperature, 40mL of water is added and the brown solution is stirred for 30 min. Afterphase separation the organic phase is washed with 15 mL of water and thesolvent is evaporated to obtain 10.6 g of compound (V) as ayellowish-brown solid (89%).

Purity by HPLC: 99.4%.

M.p.: 78-80° C.

¹H NMR (CDCl₃): 9.20 (s, 1H); 7.85 (d, J=8.7 Hz, 2H); 7.12 (d, J=8.8 Hz,2H); 2.65 (m, 6H); 1.90-0.94 (m, 18H).

EXAMPLES Example 1N-(2-butyl-3-{[4-(3-dibutylamino-propoxy)-phenyl]-hydroxymethyl}-benzofuran-5-yl)-methanesulfonamide(VI)

2.67 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.01mol, 1 eq) is dissolved in 35 mL of n-hexane and 7 mL of 2.5 M BuLihexane solution is added in 30 min during which the temperature is keptat 20° C. The reaction mixture is stirred for 2 hours at roomtemperature and then it is added to the solution of 4.37 g of4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.015 mol, 1.5 eq) in 80 mLof THF. The reaction mixture is stirred at room temperature for 2 hoursand then 40 mL of NH₄Cl solution is added. After 15 min of stirring, theproduct is extracted with 2×40 mL of diethyl ether. The organic phase isconcentrated and the crude product is purified by column chromatography(spheric silica; eluent: toluene:MTBE:methanol=50:40:10) to obtain 2.24g of compound (VI) (40%).

Purity by HPLC: 97.9%.

Molecular weight (calc): 558.7747 Da; (measured): 558.7741 Da.

¹H NMR (DMSO): 7.68 (d, J=8.5 Hz, 2H); 7.24 (m, 3H); 6.90 (d, J=8.5 Hz,2H); 5.45 (s, 1H); 4.88 (s, 1H); 4.10 (t, J=6.1 Hz, 2H); 2.90 (s, 3H);2.78 (t, J=7.0 Hz, 2H); 2.54 (t, J=7.0 Hz, 2H); 2.47 (s, 1H); 2.36 (t,J=7.0 Hz, 4H); 1.90 (m, 2H); 1.60-1.70 (m, 2H); 1.4-1.45 (m, 10H);0.8-0.9 (m, 9H).

Example 2N-(2-butyl-3-{[4-(3-dibutylamino-propoxy)-phenyl]-hydroxymethyl}-benzofuran-5-yl)-methanesulfonamide(VI)

5.34 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.02mol, 1 eq) is dissolved in 40 mL of trifluoroacetic acid and 8.7 g of4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.03 mol, 1.5 eq) is addedto the solution. The reaction mixture is heated to 40° C. and stirredfor 10 hours at this temperature. The mixture is cooled to roomtemperature and 100 mL of water is added. After 15 min of stirring, theproduct is extracted with 2×50 mL of dichloromethane. The organic phaseis concentrated and the crude product is purified by columnchromatography (spheric silica; eluent: toluene:MTBE:methanol=50:40:10)to obtain 3.68 g of compound (VI) (33%).

Purity by HPLC: 97.3%.

The product is identical with the compound prepared in Example 1.

Example 3N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide(I)

5.59 g ofN-(2-butyl-3-{[4-(3-dibutylamino-propoxy)-phenyl]-hydroxymethyl}-benzofuran-5-yl)-methanesulfonamide(VI) (0.01 mol, 1 eq) is dissolved in 30 mL of glacial acetic acid. 10mL of 2.0 M aqueous sodium hypochlorite solution is added in 30 min. Themixture is stirred for 2 hours at room temperature and then 5 mL ofsodium bisulfite solution is added. After 15 min of stirring, themixture is poured to 100 mL of water and the product is extracted with2×50 mL of dichloromethane. The solvent is evaporated and the crudeproduct is purified by column chromatography (spheric silica;eluent:toluene:ethyl acetate=70:30) to obtain 1.56 g of dronedarone (I)(28%).

Purity by HPLC: 99.3%.

¹H NMR (DMSO): 7.72 (d, J=8.6 Hz, 2H); 7.27 (m, 3H); 6.90 (d, J=8.6 Hz,2H); 5.52 (s, 1H); 4.07 (t, J=6.2 Hz, 2H); 2.91 (s, 3H); 2.78 (t, J=7.0Hz, 2H); 2.55 (t, J=7.0 Hz, 2H); 2.39 (t, J=7.0 Hz, 4H); 1.90 (m, 2H);1.60-1.70 (m, 2H); 1.4-1.45 (m, 10H); 0.8-0.9 (m, 9H).

Example 4N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]-methanesulfonamide(I)

5.59 g ofN-(2-butyl-3-{[4-(3-dibutylamino-propoxy)-phenyl]-hydroxymethyl}-benzofuran-5-yl)-methanesulfonamide(VI) (0.01 mol, 1 eq) is dissolved in 40 mL of glacial acetic acid. 15mL of 30% hydrogen peroxide solution is added in 1 hour at roomtemperature and the reaction mixture is stirred for 36 hours. 80 mL ofwater is added to the reaction mixture and the product is extracted with50 mL of dichloromethane. The organic phase is concentrated and thecrude product is purified by column chromatography (spheric silica;eluent:toluene:ethyl acetate=70:30) to obtain 4.34 g of dronedarone (I)(78%).

Purity by HPLC: 99.7%.

The product is identical with the compound prepared in Example 3.

1-2. (canceled)
 3. A compound of formula (VI) or a salt thereof

4-7. (canceled)